A biofilm is a community of sessile, stably attached microorganisms, especially bacteria, embedded in a hydrated matrix of extracellular polymeric substances exhibiting growth properties that are distinguished from those of planktonic, free-living microorganisms. Biofilms represent a target of new compositions for inhibiting, reducing, preventing, and removing microbial infections, and are believed to be partly responsible for increasing the rates of antibiotic resistance. It is thought that upwards of 60% of all nosocomial (hospital-derived) infections are due to biofilms, whose role in contaminating medical implants is now well established. Central venous catheters (CVCs) pose the greatest risk of device-related infections with infection rates of 3 to 5% and account for the most serious and costly healthcare-associated infections (See for example, Donlan and Costerton, Clin. Microbiol. Rev., Vol. 15, No. 2, pp. 167-193, 2002; Davey and O'Toole, Microbiol. Mol. Biol. Rev., Vol. 64, No. 4, pp. 847-867, 2000).
One approach to managing biofilm infections is to identify the microorganism(s) in the biofilm and to find antibiotic or biocidal agents capable of killing the microorganisms. A major limitation of this approach is that models for testing the efficacy of these agents to not sufficiently represent a biofilm environment. Biofilm bacteria can be up to 1,000-fold more resistant to antibiotic treatment than the same organism grown planktonically. Biofilm bacteria are also more resistant to biocides, such as peroxide, bleach, acids, and other biocidal agents.
In spite of the dramatic differences in susceptibility to antimicrobial agents between planktonic and sessile, biofilm microorganisms, current approaches for targeting biofilm microorganisms are insufficient in addressing this discrepancy. Antimicrobial efficacy testing often employs standard broth microdilution methods reflecting antibiotic efficacy in planktonic, rather than biofilm systems. Accordingly, broad numbers of prospective antibiotic- and biocidal agents have been identified without any expectation of success in the more “real” biofilm world.
The mechanisms by which resistance to antibiotic or biocidal agents is achieved remain subject to speculation. It is now known, however, that the structural organization of biofilms hinders the ability of antibiotics or biocides to access biofilm bacteria and can protect bacteria from a host's immune system. Clinical biofilm infections are marked by recurring symptoms after repeated antibody treatments. Such treatments typically eliminate planktonic microorganisms, but allow sessile, biofilm microorganisms to propagate and disseminate upon termination of antibiotic therapy.
In recent years, biofilm-based infections attributed to medical devices, such as catheters, prosthetic heart valves, contact lenses, and intrauterine devices have received increased attention. Despite circumstantial evidence suggesting biofilms to be a major culprit responsible for chronic wounds, their role in chronic wounds remains poorly understood.
Chronic wounds are open wounds that are recalcitrant to healing. Chronic wounds are painful, diminish the quality of life, impair mobility, and frequently lead to amputations. And they present an enormous financial toll worldwide. In 2004, diabetic foot ulcers accounted for $10 billion in direct costs (about 4% of the total personal health spending) and another $5 billion in indirect costs (disability, nursing homes, etc.). In the U.S., chronic wounds affect roughly 3 million people and are increasing at exponential rates, doubling every 4-5 years.
Chronic wounds have a number of barriers which limit healing. Many of these barriers have been extensively studied, including poor perfusion, white cell dysfunction, poor nutrition, and repetitive pressure among others. Although wound beds are known to be populated by biofilms, their role in abrogating or delaying wound healing has not yet been experimentally established. In addition, there are questions regarding the extent to which the cellular regeneration processes accompanying the healing may inadvertently provide nutritional support for sustaining biofilm viability.
In light of the foregoing, including the ongoing problems with conventional wound healing treatments, there is a need for improved compositions and methods for treating chronic wound bed biofilms and for adequately balancing the tissue regeneration demands necessary for achieving full and timely healing wounds, particularly chronic wounds.